Targeted Oncology

, Volume 8, Issue 2, pp 117–125 | Cite as

Cytokines associated with toxicity in the treatment of recurrent glioblastoma with aflibercept

  • Nicole Shonka
  • Yuji Piao
  • Mark Gilbert
  • Alfred Yung
  • Susan Chang
  • Lisa M. DeAngelis
  • Andrew B. Lassman
  • Jun Liu
  • Timothy Cloughesy
  • H. Ian Robins
  • Rita Lloyd
  • Alice Chen
  • Michael Prados
  • Patrick Y. Wen
  • John Heymach
  • John de Groot
Original Research


Plasma profiling of patients treated with antiangiogenic agents may identify markers that correlate with toxicity. Objectives were to correlate changes in cytokine and angiogenic factors as potential markers of toxicity to aflibercept. Circulating cytokine and angiogenic factors were measured in 28 patients with recurrent glioblastoma in a single-arm phase II study of aflibercept. Plasma samples were analyzed at baseline, 24 h, and 28 days using multiplex assays or ELISA. We evaluated log-transformed baseline biomarker expressions with Cox proportional hazard regression models to assess the effect of markers on any grade II–IV (Gr II–IV) toxicity, on-target toxicity (hypertension, proteinuria, thromboembolism), and fatigue. All tests were two sided with a statistical significance level of p = 0.05. Among 28 pts, there were 116 Gr II–IV events. Changes in IL-13 from baseline to 24 h predicted on-target toxicities. Increases in IL-1b, IL-6, and IL-10 at 24 h were significantly associated with fatigue. Progression-free survival was 14.9 months for patients in the all-toxicity group and 9.0 months for patients in the on-target toxicity group compared to 4.3 months for those who did not develop any Gr II–IV toxicity (p = 0.002 and p = 0.045, respectively). Toxicity from antiangiogenic therapy remains an important cause of antiangiogenic treatment discontinuation and patient morbidity. Changes in IL6, IL10, and IL13 were repeatedly correlated with toxicity. Profiling of IL-13 as a surrogate for endothelial dysfunction could individualize patients at risk during antiangiogenic therapy, as could identifying those at higher risk for fatigue using IL-6 and IL-10.


Glioblastoma Aflibercept VEGF Cytokines Toxicity 



Funding was received from the National Institutes of Health [U01-CA62399 to NABTC, 1R21A126127 to J. de G.] and the ASCO Career Development Award [to J. de G.].

Conflict of interest

We report that no funds or benefits of any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Supplementary material

11523_2013_254_MOESM1_ESM.pdf (38 kb)
ESM 1(PDF 38 kb)
11523_2013_254_MOESM2_ESM.pptx (368 kb)
Supplemental Figure 1Skin biopsy with Hematoxylin and Eosin (H&E) staining at 4× (A) and 20× (B) magnification. Histology showed psoriasiform epidermal hyperplasia with pallor of the upper epidermis, reminiscent of acrodermatitis enteropathica or other deficiency dermatosis. (PPTX 367 kb)


  1. 1.
    Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, Eichler AF, Drappatz J, Hochberg FH, Benner T, Louis DN, Cohen KS, Chea H, Exarhopoulos A, Loeffler JS, Moses MA, Ivy P, Sorensen AG, Wen PY, Jain RK (2010) Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 28(17):2817–2823CrossRefPubMedGoogle Scholar
  2. 2.
    Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733–4740CrossRefPubMedGoogle Scholar
  3. 3.
    Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27(5):740–745CrossRefPubMedGoogle Scholar
  4. 4.
    Zhu AX, Duda DG, Ancukiewicz M, di Tomaso E, Clark JW, Miksad R, Fuchs CS, Ryan DP, Jain RK (2011) Exploratory analysis of early toxicity of sunitinib in advanced hepatocellular carcinoma patients: kinetics and potential biomarker value. Clin Cancer Res 17(4):918–927. doi:10.1158/1078-0432.CCR-10-0515 CrossRefPubMedGoogle Scholar
  5. 5.
    Okunieff P, Chen Y, Maguire DJ, Huser AK (2008) Molecular markers of radiation-related normal tissue toxicity. Cancer Metastasis Rev 27(3):363–374. doi:10.1007/s10555-008-9138-7 CrossRefPubMedGoogle Scholar
  6. 6.
    Rubin P, Johnston CJ, Williams JP, McDonald S, Finkelstein JN (1995) A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys 33(1):99–109CrossRefPubMedGoogle Scholar
  7. 7.
    De Jaeger K, Seppenwoolde Y, Kampinga HH, Boersma LJ, Belderbos JS, Lebesque JV (2004) Significance of plasma transforming growth factor-beta levels in radiotherapy for non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 58(5):1378–1387. doi:10.1016/j.ijrobp.2003.09.078 CrossRefPubMedGoogle Scholar
  8. 8.
    Menard C, Johann D, Lowenthal M, Muanza T, Sproull M, Ross S, Gulley J, Petricoin E, Coleman CN, Whiteley G, Liotta L, Camphausen K (2006) Discovering clinical biomarkers of ionizing radiation exposure with serum proteomic analysis. Cancer Res 66(3):1844–1850. doi:10.1158/0008-5472.CAN-05-3466 CrossRefPubMedGoogle Scholar
  9. 9.
    Kovacs CJ, Daly BM, Evans MJ, Johnke RM, Lee TK, Karlsson UL, Allison R, Eaves GS, Biggs LM (2003) Cytokine profiles in patients receiving wide-field + prostate boost radiotherapy (xRT) for adenocarcinoma of the prostate. Cytokine 23(6):151–163CrossRefPubMedGoogle Scholar
  10. 10.
    Christensen E, Pintilie M, Evans KR, Lenarduzzi M, Menard C, Catton CN, Diamandis EP, Bristow RG (2009) Longitudinal cytokine expression during IMRT for prostate cancer and acute treatment toxicity. Clin Cancer Res 15(17):5576–5583. doi:10.1158/1078-0432.CCR-09-0245 CrossRefPubMedGoogle Scholar
  11. 11.
    Hartsell WF, Scott CB, Dundas GS, Mohiuddin M, Meredith RF, Rubin P, Weigensberg IJ (2007) Can serum markers be used to predict acute and late toxicity in patients with lung cancer? Analysis of RTOG 91-03. Am J Clin Oncol 30(4):368–376. doi:10.1097/01.coc.0000260950.44761.74 CrossRefPubMedGoogle Scholar
  12. 12.
    Wichers M, Maes M (2002) The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol 5(4):375–388. doi:10.1017/S1461145702003103 CrossRefPubMedGoogle Scholar
  13. 13.
    Ryan JL, Carroll JK, Ryan EP, Mustian KM, Fiscella K, Morrow GR (2007) Mechanisms of cancer-related fatigue. Oncologist 12(Suppl 1):22–34. doi:10.1634/theoncologist.12-S1-22 CrossRefPubMedGoogle Scholar
  14. 14.
    Souhami L, Seiferheld W, Brachman D, Podgorsak EB, Werner-Wasik M, Lustig R, Schultz CJ, Sause W, Okunieff P, Buckner J, Zamorano L, Mehta MP, Curran WJ Jr (2004) Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 60(3):853–860CrossRefPubMedGoogle Scholar
  15. 15.
    Daigle JL, Hong JH, Chiang CS, McBride WH (2001) The role of tumor necrosis factor signaling pathways in the response of murine brain to irradiation. Cancer Res 61(24):8859–8865PubMedGoogle Scholar
  16. 16.
    Schubert C, Hong S, Natarajan L, Mills PJ, Dimsdale JE (2007) The association between fatigue and inflammatory marker levels in cancer patients: a quantitative review. Brain Behav Immun 21(4):413–427. doi:10.1016/j.bbi.2006.11.004 CrossRefPubMedGoogle Scholar
  17. 17.
    Drevs J, Siegert P, Medinger M, Mross K, Strecker R, Zirrgiebel U, Harder J, Blum H, Robertson J, Jurgensmeier JM, Puchalski TA, Young H, Saunders O, Unger C (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 25(21):3045–3054. doi:10.1200/JCO.2006.07.2066 CrossRefPubMedGoogle Scholar
  18. 18.
    Rixe O, Billemont B, Izzedine H (2007) Hypertension as a predictive factor of sunitinib activity. Ann Oncol 18(6):1117CrossRefPubMedGoogle Scholar
  19. 19.
    Rixe O, Dutcher J, Motzer R, Wilding G, Stadler W, Kim S, Tarazi J, Rosbrook B, Rini B (2008) Association between diastolic blood pressure >90 mmHg and efficacy in patients with metastatic renal cell carcinoma receiving axitinib. Ann Oncol 19(8):189Google Scholar
  20. 20.
    Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J, Rosbrook B, Trask PC, Wood L, Dutcher JP (2009) Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 27(27):4462–4468. doi:10.1200/JCO.2008.21.7034 CrossRefPubMedGoogle Scholar
  21. 21.
    Rini B, Schiller J, Fruehauf J, Cohen E, Tarazi J, Rosbrook B, Ricart A, Olszanski A, Kim S, Spano J (2008) Association of diastolic blood pressure (dBP) >=90 mmHg with overall survival (OS) in patients treated with axitinib (AG-013736). J Clin Oncol 26(15):3543Google Scholar
  22. 22.
    Fruehauf J, Lutzky J, McDermott D, Brown CK, Meric JB, Rosbrook B, Shalinsky DR, Liau KF, Niethammer AG, Kim S, Rixe O (2011) Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma. Clin Cancer Res 17(23):7462–7469. doi:10.1158/1078-0432.CCR-11-0534 CrossRefPubMedGoogle Scholar
  23. 23.
    Riely G, Miller V (2007) Vascular endothelial growth factor trap in non small cell lung cancer. Clin Cancer Res 15(2):s4623–s4627CrossRefGoogle Scholar
  24. 24.
    Lockhart AC, Rothenberg ML, Dupont J, Cooper W, Chevalier P, Sternas L, Buzenet G, Koehler E, Sosman JA, Schwartz LH, Gultekin DH, Koutcher JA, Donnelly EF, Andal R, Dancy I, Spriggs DR, Tew WP (2010) Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol 28(2):207–214. doi:10.1200/JCO.2009.22.9237 CrossRefPubMedGoogle Scholar
  25. 25.
    de Groot JF, Lamborn KR, Chang SM, Gilbert MR, Cloughesy TF, Aldape K, Yao J, Jackson EF, Lieberman F, Robins HI, Mehta MP, Lassman AB, Deangelis LM, Yung WK, Chen A, Prados MD, Wen PY (2011) Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study. J Clin Oncol 29(19):2689–2695. doi:10.1200/JCO.2010.34.1636 CrossRefPubMedGoogle Scholar
  26. 26.
    de Groot JF, Piao Y, Tran H, Gilbert M, Wu HK, Liu J, Bekele BN, Cloughesy T, Mehta M, Robins HI, Lassman A, DeAngelis L, Camphausen K, Chen A, Yung WK, Prados M, Wen PY, Heymach JV (2011) Myeloid biomarkers associated with glioblastoma response to anti-VEGF therapy with aflibercept. Clin Cancer Res 17(14):4872–4881. doi:10.1158/1078-0432.CCR-11-0271 CrossRefPubMedGoogle Scholar
  27. 27.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) Reporting recommendations for tumor marker prognostic studies (remark). Exp Oncol 28(2):99–105PubMedGoogle Scholar
  28. 28.
    Shamay Y, Paulin D, Ashkenasy G, David A (2009) E-selectin binding peptide-polymer-drug conjugates and their selective cytotoxicity against vascular endothelial cells. Biomaterials 30(32):6460–6468. doi:10.1016/j.biomaterials.2009.08.013 CrossRefPubMedGoogle Scholar
  29. 29.
    Wynn TA (2003) IL-13 effector functions. Annu Rev Immunol 21:425–456. doi:10.1146/annurev.immunol.21.120601.141142 CrossRefPubMedGoogle Scholar
  30. 30.
    Saito A, Okazaki H, Sugawara I, Yamamoto K, Takizawa H (2003) Potential action of IL-4 and IL-13 as fibrogenic factors on lung fibroblasts in vitro. Int Arch Allergy Immunol 132(2):168–176. doi:73718 CrossRefPubMedGoogle Scholar
  31. 31.
    Van Cutsem E TJ, Lakomy R (2011) Intravenous aflibercept versus placebo in combination with irinotecan/5-FU (FOLFIRI) for second-line treatment of metastatic colorectal cancer (MCRC): results of a multinational phase III trial (EFC10262-VELOUR) Ann Oncol 22Google Scholar
  32. 32.
    Coleman RL, Duska LR, Ramirez PT, Heymach JV, Kamat AA, Modesitt SC, Schmeler KM, Iyer RB, Garcia ME, Miller DL, Jackson EF, Ng CS, Kundra V, Jaffe R, Sood AK (2011) Phase 1–2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer. Lancet Oncol 12(12):1109–1117. doi:10.1016/S1470-2045(11)70244-3 CrossRefPubMedGoogle Scholar
  33. 33.
    Colombo N, Mangili G, Mammoliti S, Kalling M, Tholander B, Sternas L, Buzenet G, Chamberlain D (2012) A phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites. Gynecol Oncol 125(1):42–47. doi:10.1016/j.ygyno.2011.11.021 CrossRefPubMedGoogle Scholar
  34. 34.
    Zhu AX, Duda DG, Sahani DV, Jain RK (2009) Development of sunitinib in hepatocellular carcinoma: rationale, early clinical experience, and correlative studies. Cancer J 15(4):263–268. doi:10.1097/PPO.0b013e3181af5e35 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag France 2013

Authors and Affiliations

  • Nicole Shonka
    • 1
  • Yuji Piao
    • 2
  • Mark Gilbert
    • 2
  • Alfred Yung
    • 2
  • Susan Chang
    • 3
  • Lisa M. DeAngelis
    • 4
  • Andrew B. Lassman
    • 5
  • Jun Liu
    • 2
  • Timothy Cloughesy
    • 6
  • H. Ian Robins
    • 7
  • Rita Lloyd
    • 7
  • Alice Chen
    • 8
  • Michael Prados
    • 3
  • Patrick Y. Wen
    • 9
  • John Heymach
    • 2
  • John de Groot
    • 2
  1. 1.Division of Oncology and HematologyUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.M.D. Anderson Cancer CenterUniversity of TexasHoustonUSA
  3. 3.University of California San FranciscoSan FranciscoUSA
  4. 4.Memorial Sloan Kettering Cancer CenterNew YorkUSA
  5. 5.Department of Neurology and Herbert Irving Comprehensive Cancer CenterNew York-Presbyterian/Columbia University Medical CenterNew YorkUSA
  6. 6.University of California Los AngelesLos AngelesUSA
  7. 7.University of Wisconsin Medical SchoolMadisonUSA
  8. 8.NIH, NCI and CTEPBethesdaUSA
  9. 9.Dana Farber Cancer InstituteBostonUSA

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